The proposed research will examine the role of social/emotional factors in atherosclerosis, and attempt to establish mechanistic links among biobehavioral risk factors, molecular mediators and clinical disease progression. This will be accomplished through the use of the Watanabe Heritable Hyperlipidemic Rabbit (WHHL), a genetic animal model characterized by hyperlipidemia and severe atherosclerosis. We have demonstrated that social environment profoundly affects the course of disease in WHHLs, such that animals in stable relationships with littermates, as opposed to WHHLs in unstable social conditions or social isolation, showed a significant decrease in the progression of atherosclerosis. An unstable social environment, characterized by agonistic behavior and emotional stress, was associated with the development of severe, advanced atherosclerotic lesions. These findings suggest that biobehavioral factors are important in the progression of atherosclerosis, even in models of disease that have strong genetic determinants. It is well established that hyperlipidemia, inflammation and oxidative stress are the proximal vascular mechanisms in atherosclerosis, but the mediators linking social/emotional behavior to these drivers of disease are not clear. One of the most likely mediators linking social environment to disease is the sympathetic nervous system (SNS), and in preliminary work, we have observed that there is SNS hyperinnervation in atherosclerotic vascular tissue. This chronic SNS structural plasticity is proposed to exacerbate vascular inflammation, oxidative stress, and the progression of atherosclerosis. The proposed work will examine whether this SNS remodeling occurs in response to social environment or to the presence of local disease. We will also assess whether preventing this SNS hyperinnervation attenuates vascular inflammation and the progression of atherosclerosis. Therefore, the specific aims of the project are: 1a.) to examine SNS innervation density of vascular tissue in WHHLs vs normolipidemic control rabbits (New Zealand White; NZW) over time as a function of social environment, and to relate these differences to the progression of atherosclerosis, 1b.) to examine SNS innervation density of other peripheral tissue in WHHLs vs NZWs as a function of social environment, and 2.) to quantify vascular SNS innervation density, inflammation and atherosclerosis in WHHLs following pharmacological antagonism of NGF's target receptor, TrkA. The proposed research represents a novel approach to understanding how known risk factors (e.g., hyperlipidemia) may interact with behavioral variables to lead to the exacerbation or attenuation of disease. This type of SNS neuronal plasticity, and the resulting enhanced vascular inflammation/oxidative stress, may represent intervention targets for behavioral and/or pharmacological therapy in cardiovascular disease.